Abstract
Osteosarcoma (OS) is the most common type of solid bone cancer and remains the second leading cause of cancer-related death for children and young adults. Hypoxia is an element intrinsic to most solid-tumor microenvironments, including that of OS, and is associated with resistance to therapy, poor survival, and a malignant phenotype. Cells respond to hypoxia through alterations in gene expression, mediated most notably through the hypoxia-inducible factor (HIF) class of transcription factors. Here we investigate hypoxia-induced changes in the Wnt/β-catenin signaling pathway, a key signaling cascade involved in OS pathogenesis. We show that hypoxia results in increased expression and signaling activation of HIF proteins in human osteosarcoma cells. Wnt/β-catenin signaling is down-regulated by hypoxia in human OS cells, as demonstrated by decreased active β-catenin protein levels and axin2 mRNA expression (p<0.05). This down-regulation appears to rely on both HIF-independent and HIF-dependent mechanisms, with HIF-1α standing out as an important regulator. Finally, we show that hypoxia results in resistance of human OS cells to doxorubicin-mediated toxicity (6–13 fold increase, p<0.01). These hypoxic OS cells can be sensitized to doxorubicin treatment by further inhibition of the Wnt/β-catenin signaling pathway (p<0.05). These data support the conclusion that Wnt/β-catenin signaling is down-regulated in human OS cells under hypoxia and that this signaling alteration may represent a viable target to combat chemoresistant OS subpopulations in a hypoxic niche.
Highlights
Osteosarcoma (OS) is the most common type of solid bone cancer, mainly arising in children and young adults, and it remains the second leading cause of cancer-related death in this age group [1]
Hypoxic regions have been identified in human osteosarcomas, and increased levels of hypoxia-inducible factor (HIF)-1a are correlated with decreased disease-free survival and overall survival, as well as increased microvessel density and surgical stage [9,10]
When we examined HIF protein expression at shorter time points in the MNNG/HOS cell line, we found that both HIF-1a and HIF-2a were induced by culturing cells under hypoxic conditions for increasing time periods (Figure 1B)
Summary
Osteosarcoma (OS) is the most common type of solid bone cancer, mainly arising in children and young adults, and it remains the second leading cause of cancer-related death in this age group [1]. Osteosarcomas are aggressive, high-grade tumors, with about 20% of patients presenting with metastases [1]. Hypoxia is intrinsic to most solid-tumor microenvironments and is associated with resistance to therapy, poor survival, and a malignant phenotype [4]. HIF itself is a heterodimeric transcription factor comprising an oxygen-sensitive a-subunit and a constitutively expressed bsubunit [6]. The lack of O2 prevents this hydroxylation, and heterodimerized HIF enters the nucleus to bind to hypoxia response elements and function as a transcription factor by interacting with other coactivators such as CBP/p300 [7]. Signaling responses governed by HIFs have been studied extensively in different cancers, little is known about the contributing mechanisms of hypoxia-associated therapy resistance in OS and whether or not they are related to HIFs
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